Due to the pandemic caused by COVID-19, interest has been high in drugs that may have the potential to treat COVID-19. The analysis below discusses possible treatments for COVID-19 and what is known about associated evergreening behavior (sourced from C4i’s Evergreen Drug Patent Search).
The following drugs are discussed in this section. Those in boldface represent drugs that have strong evidence of evergreening behavior because there is at least one patent cliff extension associated with the drug. The exception is Remdesivir, which is not yet approved by the FDA and thus does not show up in the dataset. It is included because its maker, Gilead, applied for an Orphan Drug designation for the drug, which can be another strategy of evergreening.
- Remdesivir
- Hydroxychloroquine (brand name: Plaquenil)
- Chloroquine
- Azithromycin (brand names: Zithromax, Zmax, Azasite)
- Lopinavir; Ritonavir (brand name: Kaletra)
- Tocilizumab (brand name: Actemra)
- Sarilumab (brand name: Kevzara)
- Bacillus Calmette-Guerin (BCG) vaccine
- Pirfenidone (brand name: Esbriet)
- Sofosbuvir / Daclatsivir
- Dexamethasone
Remdesivir is an antiviral drug that failed as an Ebola treatment. It never received FDA approval, so it is not listed in the Orange Book. Its maker, Gilead, is conducting clinical trials and was making it available on a compassionate use program (recently suspended due to overwhelming demand). Gilead applied for an orphan drug designation for the drug in early March 2020, but was shamed into giving it up.
Hydroxychloroquine and chloroquine are drugs approved for treating and preventing malaria. Hydroxychloroquine can also treat arthritis and lupus. All versions of chloroquine available on the market currently are generic, so they are not in the database. There is one brand version of hydroxychloroquine called Plaquenil that is currently on the market but is not in the dataset either – it was approved before 2005 and did not have any patent or exclusivity additions since then.
One study reported hydroxychloroquine in combination with azithromycin, an antibiotic, may also help treat the disease. Some doctors are using this combination to treat COVID patients. There are 3 brands of azithromycin that show up in the database – Zithromax, Zmax, and Azasite. None of them seem to have evergreening behavior, but there are 6 New Drug Applications associated with Zithromax, all owned by Pfizer. Zmax is owned by a Pfizer subsidiary.
Lopinavir-ritonavir, an HIV drug, was tested in clinical trials in China but didn’t show promise. However, the trial was underpowered and is currently under investigation in a World Health Organization study. A version of the drug in the US has a list price of $503, compared to the lowest list price of $9 outside of the US. Furthermore, the drug’s estimated cost of production is only $0.28 for one day, or $4 for a 14-day course treatment.
The brand name is Kaletra, and all New Drug Applications are owned by AbbVie. There is evidence of some evergreening behavior related to Kaletra:
Active ingredient: Lopinavir; Ritonavir
Drug name: Kaletra
Company: AbbVie
NDA: 21226
-
- Num. Protections: 64
- Approval date: September 2000
- Latest prot. date: November 2020
- Months of extra prot time: 151
- Unique patents: 17
- Patent cliff extensions: 2
Company: AbbVie
NDA: 21251
-
- Num. Protections: 66
- Approval date: September 2000
- Latest prot. date: May 2022
- Months of extra prot time: 197
- Unique patents: 14
- Patent cliff extensions: 2
Company:AbbVie
NDA:21906
-
- Num. Protections: 77
- Approval date: October 2005
- Latest prot. date: June 2028
- Months of extra prot time: 186
- Unique patents: 20
- Patent cliff extensions: 7
Other drugs approved to treat arthritis may work to treat the virus by suppressing the immune system, which overreacts in response to the virus and damages the body. These drugs are Actemra and Kevzara. However, they’re biologic drugs and thus are not in the database, which focuses exclusively on small molecule drugs.
The Bacillus Calmette-Guerin (BCG) vaccine treats tuberculosis in countries with high risk of catching the disease and thus is not generally recommended in the US. One of the “off-target” benefits of the vaccine is helping the immune system fight off pathogens, which may include the COVID-19 virus. While the World Health Organization concluded there is currently no evidence that the vaccine prevents COVID-19, there is hope that research into the vaccine can prove protection and benefit frontline health workers. The vaccine is a weakened form of the live bacteria that causes tuberculosis and is thus not considered a drug product that would be registered to the Orange Book. It does not show up in the database.
Pirfenidone treats a type of lung disease called idiopathic pulmonary fibrosis. The drug is currently under clinical trial investigation. A version of the drug in the US has a list price of $9606, compared to the lowest list price of $100 outside of the US. Furthermore, the drug’s estimated cost of production is only $1.09 for one day, or $31 for a 28-day course treatment.
The brand name is Esbriet, and both NDAs are owned by Genentech. There is evidence for evergreening behavior related to Esbriet:
Active ingredient:Pirfenidone
Drug name: Esbriet
Company:Genentech
NDA: 22535*
-
- Num. Protections: 25
- Approval date: October 2014
- Latest prot. date: August 2033
- Months of extra prot time: 166
- Unique patents: 20
- Patent cliff extensions: 1
*This NDA also has an Orphan Drug exclusivity.
Company: Genentech
NDA: 208780*
-
- Num. Protections: 93
- Approval date: January 2017
- Latest prot. date: August 2033
- Months of extra prot time: 188
- Unique patents: 16
- Patent cliff extensions: 1
*This NDA also has an Orphan Drug exclusivity.
Sofosbuvir/daclatsivir is a combination antiviral drug used to treat hepatitis C. The drug in the US has a list price of $18,610, compared to the lowest list price of $6 outside the US. Furthermore, the drug’s estimated cost of production is only $0.39 for one day or $5 for a 14-day course treatment.
The combination drug does not show up in the database, but the separate ingredients do. Sofosbuvir by itself is available as a brand drug called Sovaldi, which is owned by Gilead. There is evidence of evergreening behavior related to Sovaldi:
Active ingredient: Sofosbuvir
Drug name: Sovaldi
Company: Gilead
NDA: 204671
-
- Num. Protections: 10
- Approval date: December 2013
- Latest prot. date: December 2030
- Months of extra prot time: 144
- Unique patents: 9
- Patent cliff extensions: 1
Daclatsivir by itself is available as a brand drug called Daklinza, owned by Bristol Myers-Squibb. Daklinza is used in combination with other drugs, including sofosbuvir, to treat hepatitis C. There is evidence of evergreening behavior related to Daklinza:
Active ingredient: Daclatsivir dihydrochloride
Drug name: Daklinza
Company: Bristol Myers-Squibb
NDA: 206843
-
- Num. Protections: 13
- Approval date: July 2015
- Latest prot. date: June 2031
- Months of extra prot time: 148
- Unique patents: 5
- Patent cliff extensions: 1
Dexamethasone is a steroid drug that recently showed evidence of reducing death rates in COVID patients receiving ventilation or oxygen. The data has not been peer-reviewed yet, but UK regulators have granted approval for dexamethasone to be used in hospitalized patients requiring oxygen. There are 2 brands of dexamethasone (ignoring combination drugs with dexamethasone) that show up in the database – Ozurdex and Dexycu Kit. There is evidence for evergreening behavior related to both:
Active ingredient: Dexamethasone
Drug name: Ozurdex
Company: Allergan
NDA: 22315
-
- Num. Protections: 38
- Approval date: June 2009
- Latest prot. date: November 2023
- Months of extra prot time: 137
- Unique patents: 38
- Patent cliff extensions: 2
Company: Eyepoint Pharms
NDA: 208912
-
- Num. Protections: 5
- Approval date: February 2018
- Latest prot. date: May 2034
- Months of extra prot time: 164
- Unique patents: 4
- Patent cliff extensions: 1
Conclusion
With the ongoing COVID-19 pandemic, there has been an increased and focused interest in drugs that can help treat or even prevent the disease. Even when a drug is approved to treat COVID-19, barriers to access still exist, an important one being the cost of these drugs.
Generic competition is essential for competitive pricing in the drug marketplace, but companies use evergreening strategies to fend off generic competition. Thus, evergreening contributes to the high cost of drugs and lack of access to those who especially need it.
The Center for Innovation at UC Law’s Evergreen Drug Patent Search can help identify potential evergreening behavior associated with existing drugs, including those that are being investigated as treatments for COVID-19. The volume of patents or exclusivities added, which increases the obstacles a generic must overcome to gain market entry, can be gleaned from the number of protections, and the number of unique patents that a drug has. Additional patents and exclusivities can also extend the amount of time a drug is protected, which can be gleaned from the months of extra protection time and the number of patent cliff extensions associated with a drug.
We hope that policymakers and other stakeholders use this information to identify potential problems with evergreening and develop new solutions so that anyone and everyone can access the basic life-saving medication that they need.
References
Helen Branswell, Why a decades-old TB vaccine is getting attention in the fight against Covid-19, STAT News, https://www.statnews.com/2020/04/14/decades-old-tb-vaccine-attracts-attention-and-skepticism-as-a-potential-weapon-against-covid-19/ (Apr. 14, 2020).
Mona Chalabi, Soaring drug prices could bar access to future coronavirus treatments, The Guardian, https://www.theguardian.com/world/2020/may/11/soaring-drug-prices-could-bar-access-to-future-coronavirus-treatments (May 11, 2020).
Matthew Herper, When might experimental drugs to treat Covid-19 be ready? A forecast, STAT News, https://www.statnews.com/2020/03/24/when-might-experimental-drugs-to-treat-covid-19-be-ready-a-forecast/ (Mar. 24, 2020).
Information for Clinicians on Investigational Therapeutics for Patients with COVID-19, CDC, https://www.cdc.gov/coronavirus/2019-ncov/hcp/therapeutic-options.html (last updated Apr. 25, 2020).
Angus Liu, New dexamethasone stats suggest life-saving potential for severe COVID-19 patients, FiercePharma, https://www.fiercepharma.com/